title: Host-Mycobacterium avium subsp. paratuberculosis interactome reveals a novel iron assimilation mechanism linked to nitric oxide stress during early infection.
abstract: BACKGROUND
  The initial interaction between host cell and pathogen sets the stage for the ensuing infection and ultimately determine the course of disease. However, there is limited knowledge of the transcripts utilized by host and pathogen and how they may impact one another during this critical step. The purpose of this study was to create a host-Mycobacterium avium subsp. paratuberculosis (MAP) interactome for early infection in an epithelium-macrophage co-culture system using RNA-seq.
  
  
  RESULTS
  Establishment of the host-MAP interactome revealed a novel iron assimilation system for carboxymycobactin. Iron assimilation is linked to nitric oxide synthase-2 production by the host and subsequent nitric oxide buildup. Iron limitation as well as nitric oxide is a prompt for MAP to enter into an iron sequestration program. This new iron sequestration program provides an explanation for mycobactin independence in some MAP strains grown in vitro as well as during infection within the host cell. Utilization of such a pathway is likely to aid MAP establishment and long-term survival within the host.
  
  
  CONCLUSIONS
  The host-MAP interactome identified a number of metabolic, DNA repair and virulence genes worthy for consideration as novel drug targets as well as future pathogenesis studies. Reported interactome data may also be utilized to conduct focused, hypothesis-driven research. Co-culture of uninfected bovine epithelial cells (MAC-T) and primary bovine macrophages creates a tolerant genotype as demonstrated by downregulation of inflammatory pathways. This co-culture system may serve as a model to investigate other bovine enteric pathogens.
authors.affiliation: Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, 1971 Commonwealth Avenue, Saint Paul, MN 55108, USA. lamo0062@umn.edu.
authors.forename: Elise A
authors.initials: EA
authors.lastname: Lamont
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Xu
authors.forename: Srinand
authors.initials: S
authors.lastname: Sreevatsan
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002417:Cattle; D002473:Cell Wall / Q000378:metabolism; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000382:microbiology; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D054884:Host-Pathogen Interactions; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D050356:Lipid Metabolism; D008264:Macrophages / Q000382:microbiology; D053858:Metabolic Networks and Pathways; D016927:Mycobacterium avium subsp. paratuberculosis / Q000502:physiology*; D009532:Nickel / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D010283:Paratuberculosis / Q000382:microbiology*; D060888:Real-Time Polymerase Chain Reaction; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013312:Stress, Physiological; D059467:Transcriptome
chemical_list: D001426:Bacterial Proteins; D011951:Receptors, Complement; D009569:Nitric Oxide; D009532:Nickel; D007372:Interferons; D007501:Iron